1. Field of the Invention
This invention relates to the administration of pharmaceuticals which are active when delivered to the lung as an aerosol.
Certain medications, especially those intended for the treatment of acute and chronic respiratory disorders, are most effective when inhaled directly into the lungs. Thus, numerous pharmaceutical products are marketed as aerosols administered from metered dose inhalers.
While aerosol therapies have been very successful, there have been a number of difficulties in dispensing the aerosols properly.
A major problem of aerosol therapy is achieving deposition of the aerosol on the walls of small bronchi and bronchioles, where the action of the medication is most often required. Less than ten percent of the medication delivered by standard metered dose inhalers reaches the typical patient's lungs. Most of the ninety percent of the medication which does not penetrate to the target area is deposited in the mouth, throat, and trachea, and is eventually ingested. A small fraction of the aerosol is exhaled. The medication which deposits in the mouth and throat may lead to dysphonia and/or oral and laryngeal candidiasis while the medication which is ingested serves no medical purpose to the patient and is responsible only for undesirable side effects.
Therefore the delivery of same drugs via aerosol has been considered impractical. Nevertheless the aerosol delivery of many drugs, if possible, would present an attractive alternative to the therapies that are currently available. An example of such a substance is polypeptide.
Polypeptides are made up of amino acid sequences, and include large molecules like insulin, and all of the products of recombinant DNA (rDNA) techniques. These molecules are broken down in the digestive tract and, therefore, the intact polypeptide molecule is not absorbed into the bloodstream. Accordingly, the only practical way to administer these drugs is by injection, although the nasal route of administration would be desirable and has been suggested, but has not been practical.
Another example is tissue plasminogen activator (t-PA) which appears to be successful in halting damage done to cardiac muscle during myocardial infarction. There could be an advantage to being able to utilize this drug as an aerosol for inhalation so that it could be administered without the need to wait for a physician or paramedic.
Delivery of therapy in pneumonia directly to the lung would also be desirable. Ordinarily, the concentration of antibiotic in the sputum is only two to three percent of the concentration in blood. However, in pneumonia, antibiotic concentration in the sputum is believed to be the determining factor for efficacy of the therapy. Therefore, direct delivery of the antibiotic may improve the effectiveness of the treatment.
In order to avoid the problems encountered with aerosol delivery, noted above, the aerosol should consist of small particles, less than 5 microns, since larger particles cannot negotiate the sharp turns to the lung and are deposited in the oropharynx due to inertial effects. Particles that persist in the airstream beyond the oropharynx may deposit in the larynx and on the walls of the trachea and large bronchi as a result of turbulence, particularly if the patient inhales at a volumetric flow rate above 30 liters per minute.
Metered dose inhalers deliver aerosol at a very high velocity directly into the patient's mouth, and most of the medication impacts and is deposited in the mouth. This high initial velocity of the aerosol is a major factor in the ineffectiveness of many inhaler systems. In order to minimize mouth deposition it has been determined that the volumetric flow rate of the inhaled aerosol should be below 30 liters per minute.
After the medication has been inhaled it is best to continue inhaling to total lung capacity to promote greater penetration of drug to the lung periphery. One should then hold that breath for four to ten seconds, if possible, to allow for sedimentation of particles onto the airway surface.
Several pharmaceutical manufacturers have included, or sold separately with their aerosol products, what they refer to variously as "spacers", "inhalers", "drug inhalers", "oral adapters", "spacer-inhalers", and "spray inhalers" to be used in conjunction with their products.
Of the related devices known to the inventors, only Sackner et al., U.S. Pat. No. 4,484,577, marketed as the INSPIREASE.TM. from Key Pharmaceutical, addresses the known problems of aerosol inhalation. The INSPIREASE.TM. is essentially a collapsible bag into which the medication is metered, and from which the patient inhales. The INSPIREASE.TM. mouthpiece contains a whistle which is silent at low flow rates but sounds when the patient is inhaling too rapidly.
Further, laboratory equipment has been developed which allows inspired air to be measured using a pneumotachograph. The flow rate signal is integrated by a computer, and an aerosol canister containing the medication is actuated automatically at a predetermined lung volume using a solenoid mounted on top of the aerosol actuator. While this system is suitable for experimental studies, it is impractical for use in routine therapy because of size and cost.
Thus, there is a need for a device to aid patients in taking their aerosol medications. The device should limit the volumetric flow rate of the medication and aerosol as they enter the mouth, and should allow the medication to be inhaled at a predetermined point in the respiratory cycle. It should be possible to inhale to maximum capacity.
The size of the device should allow it to be carried by the patient without too much inconvenience, and the cost to the patient should be low.